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Exploring the mechanism of AGR2 regulating the progression of pancreatic ductal adenocarcinoma and remodeling of the tumor microenvironment

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is a highly invasive and lethal malignant tumor characterized by extensive desmoplasia. We found that AGR2 deletion reshapes the tumor microenvironment by affecting the activation of the IGF1 signaling pathway. On the one hand, AGR2, as an endoplasmic reticulum protein, promoted correct folding and cell surface distribution of IGF1R. On the other hand, AGR2 was secreted into the extracellular space, promoting IGF1 transcription by activating the WNT pathway in cancer-associated fibroblasts (CAFs). Through these mechanisms, AGR2 significantly enhanced the IGF1 signal in the PDAC tumor microenvironment, accelerating the formation of desmoplasia and an immunosuppressive microenvironment.

ORGANISM(S): Homo sapiens

PROVIDER: GSE267820 | GEO | 2024/11/26

REPOSITORIES: GEO

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Exploring the mechanism of AGR2 regulating the progression of pancreatic ductal adenocarcinoma and remodeling of the tumor microenvironment [CUT&Tag]

Project description:Pancreatic ductal adenocarcinoma (PDAC) is a highly invasive and lethal malignant tumor characterized by extensive desmoplasia. We found that AGR2 deletion reshapes the tumor microenvironment by affecting the activation of the IGF1 signaling pathway. On the one hand, AGR2, as an endoplasmic reticulum protein, promoted correct folding and cell surface distribution of IGF1R. On the other hand, AGR2 was secreted into the extracellular space, promoting IGF1 transcription by activating the WNT pathway in cancer-associated fibroblasts (CAFs). Through these mechanisms, AGR2 significantly enhanced the IGF1 signal in the PDAC tumor microenvironment, accelerating the formation of desmoplasia and an immunosuppressive microenvironment.

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Paradoxical drug sensitization of lung cancer cells by stromal fibroblast-secreted IGF-binding proteins: Phosphotyrosine Profiling

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2023-03-11 | PXD023692 | Pride

Paradoxical drug sensitization of lung cancer cells by stromal fibroblast-secreted IGF-binding proteins: Secretomics

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Gene expression profile of the stomach from an AGR2 null mouse

2012-12-01 | GSE40062 | GEO

Genes regulated by AGR2 in pancreatic cancer cell lines FA6 and MiaPaCa2

Project description:We and others have shown that AGR2 is frequently upregulated during the development of pancreatic cancer. We used microarray to look at the target genes regulated by AGR2 in pancreatic cancer cell lines FA6 and MiaPaCa2. Keywords: gene knock-down, overexpression We transiently down-regulated AGR2 expression in FA6 pancreatic cancer cells using INTERFERin transfection reagent and either AGR2 siRNA or non-targeting control siRNA for 48 hours. RNA was extracted and hybridized on Affymetrix microarrays. We looked for new target genes regulated by AGR2. We generated stable cell lines by introducing control vector pCEP4 or AGR2 overexpressing vector pCEP4-AGR2 into the pancreatic cancer cell line MiaPaCa2, single cell clones were then isolated. RNA was extracted and hybridized on Affymetrix microarrays.We looked for new target genes regulated by AGR2.

2013-07-28 | E-GEOD-12513 | biostudies-arrayexpress

The protein disulfide isomerase AGR2 is essential for the production of intestinal mucus

Project description:Protein disulfide isomerases (PDIs) aid protein folding and assembly by catalyzing formation and shuffling of cysteine disulfide bonds in the endoplasmic reticulum (ER). Many members of the PDI family are expressed in mammals but the roles of specific PDIs in vivo are poorly understood. A recent homology-based search for additional PDI family members identified anterior gradient homolog 2 (AGR2), a protein originally presumed to be secreted by intestinal epithelial cells, but the function of AGR2 has been obscure. Here we show that AGR2 is expressed in the ER of secretory cells and is essential for in vivo production of intestinal mucin, a large cysteine-rich glycoprotein that forms the protective mucus gel lining the intestine. A cysteine residue within the AGR2 thioredoxin-like domain forms mixed disulfide bonds with MUC2, consistent with a direct role for AGR2 in mucin processing. Despite a complete absence of intestinal mucin, mice lacking AGR2 appeared healthy but were highly susceptible to dextran sodium sulfate-induced experimental colitis, indicating a critical role for AGR2 in protection from environmental insults. We conclude that AGR2 is a unique member of the PDI family that has a specialized and non-redundant role in intestinal mucus production. Keywords: small intestine and colon gene expression profiles for Agr2-/- and littermate control mice

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Gene expression profile of the stomach from an AGR2 null mouse

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Transcription profiling of mouse ventricles of IGF1R, IGF1R-caPI3K, IGF1R-dnPI3K, caPI3K, dnPI3K transgenic female mice at 3 months of age vs. non transgenic littermate controls

Project description:IGF1 and IGF1 receptors (IGF1R) are present in the adult heart and have been shown to be essential for myocardial performance. Insulin-like growth factor 1 (IGF1) is produced in numerous tissues particularly by the liver in response to growth hormone stimulation and is an important factor in the regulation of post-natal growth and development. We have generated and characterized transgenic mice over-expressing the IGF1R. We crossed IGF1R transgenic mice with dominant negative (dn)PI3K (p110) and with constitutively active (ca)PI3K(p110) transgenic mice. Expression profiling was performed on the ventricles of IGF1R, IGF1R-caPI3K, IGF1R-dnPI3K, caPI3K, dnPI3K transgenic female mice at 3 months of age. Non-transgenic littermates were used as controls.

2007-09-29 | E-GEOD-1143 | biostudies-arrayexpress

Genes regulated by AGR2 in pancreatic cancer cell lines FA6 and MiaPaCa2

2013-07-28 | GSE12513 | GEO

Secretome profiling of canine mammary tumor cells reveals AGR2-mediated regulation of protein secretion

Project description:Canine mammary tumors (CMTs) in intact female dogs serve as a valuable natural model for understanding human cancers. Our previous findings identified the overexpression of Anterior Gradient 2 (AGR2) in CMT tissues compared to normal mammary glands, highlighting its association with CMT progression. We observed that enhanced AGR2 expression actively promotes CMT cell chemotaxis by modulating the extracellular milieu. To decipher the AGR2-affected secretome associated with chemotaxis, we utilized gel-enhanced liquid chromatography-tandem mass spectrometry (GeLC-MS/MS) to scrutinize the conditioned media (CM) of AGR2-expressing CMT-U27 and CF41.Mg cells in comparison to the respective vector-expressing controls. In total, 798 proteins in CMT-U27 and 788 proteins in CF41.Mg were successfully identified and quantified. Among these proteins, 51 and 40 CM proteins were identified as AGR2-increased, while 28 and 50 CM proteins were designated as AGR2-decreased, respectively. Intriguingly, seven CM proteins exhibited increased abundance in both CMT-U27 and CF41.Mg cells, including AGR2, 14-3-3ε (gene name: YWHAE), and α-Actinin-4 (ACTN4). Ectopic AGR2 expression significantly increases the release of 14-3-3ε and ACTN4 in the CM. Conversely, knockdown or knockout of AGR2 expression remarkably reduces their release. AGR2 controls the release of 14-3-3ε and ACTN4, responsive to activation of ER stress and autophagy. Finally, depleting extracellular 14-3-3ε or ACTN4 reduces the AGR2-modulated CM chemotaxis. Our study uncovers the novel extracellular pro-oncogenic functions of 14-3-3ε and ACTN4 in the AGR2-modulated microenvironment.

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